Perhaps some of you have already seen this. May be of interest....
http://www.marketwatch.com/story/aa...-evidence-of-reduced-complications-2013-05-06
http://www.marketwatch.com/story/aa...-evidence-of-reduced-complications-2013-05-06
Latest on ProAct for Reduced Anticoagulation with On-X valve
- Thread starter Roberta
- Start date
Help Support Valve Replacement Forums:
pellicle
Professional Dingbat, Guru and Merkintologist
Thanks for posting that Roberta
For all of it there seemed only one small bit of information:
With nothing mentioned about thromboembolic related problems...
None the less it does ease my mind about dropping a little out of range
For all of it there seemed only one small bit of information:
With nothing mentioned about thromboembolic related problems...
None the less it does ease my mind about dropping a little out of range
http://aats.org/annualmeeting/Program-Books/2013/1.cgi
Good point Pellicle. The study summary from the AATS annual meeting is more specific (see above link):
Results: 375 AVR patients were randomized into control (190) and treatment (185) groups between September 2006 and December 2009. Mean age was 55.2 + 12.5 yrs; 79% were male; 93% were in sinus rhythm preoperatively. Calcific degeneration was the native valve pathology in 67%; patients with active endocarditis were excluded. Concomitant procedures included CABG (27%), aortic aneurysm repair (14%) and other procedures (25%). Follow-up averaged 3.42 years (675.3 pt-yrs control and 606.4 pt-yrs treatment). Mean INR (+ STD) was 2.50 + 0.63 for the control and 1.89 + 0.49 for the treatment group (p<0.0001). As shown in the table the treatment group experienced significantly lower major and minor bleeding event rates in %/ptyr. There was no significant difference in incidence of stroke, transient ischemic attack (TIA) or total neurological events. All-cause mortality was similar between groups.Conclusions: INR may be maintained safely between 1.5-2.0 in AVR patients after implantation of this approved bileaflet mechanical prosthesis. In combination with low-dose aspirin, this therapy resulted in significantly lower risk of bleeding than customary INR 2.0-3.0, without significant increase in TE.
Good point Pellicle. The study summary from the AATS annual meeting is more specific (see above link):
Results: 375 AVR patients were randomized into control (190) and treatment (185) groups between September 2006 and December 2009. Mean age was 55.2 + 12.5 yrs; 79% were male; 93% were in sinus rhythm preoperatively. Calcific degeneration was the native valve pathology in 67%; patients with active endocarditis were excluded. Concomitant procedures included CABG (27%), aortic aneurysm repair (14%) and other procedures (25%). Follow-up averaged 3.42 years (675.3 pt-yrs control and 606.4 pt-yrs treatment). Mean INR (+ STD) was 2.50 + 0.63 for the control and 1.89 + 0.49 for the treatment group (p<0.0001). As shown in the table the treatment group experienced significantly lower major and minor bleeding event rates in %/ptyr. There was no significant difference in incidence of stroke, transient ischemic attack (TIA) or total neurological events. All-cause mortality was similar between groups.Conclusions: INR may be maintained safely between 1.5-2.0 in AVR patients after implantation of this approved bileaflet mechanical prosthesis. In combination with low-dose aspirin, this therapy resulted in significantly lower risk of bleeding than customary INR 2.0-3.0, without significant increase in TE.
Last edited:
pellicle
Professional Dingbat, Guru and Merkintologist
Thanks heaps for this extra info 
I feel a little abashed that I didn't fish it out myself .. my excuse is that I'm working on my bike at the moment (well now I'm making dinner, but anyway)
Like this information a lot.
I feel a little abashed that I didn't fish it out myself .. my excuse is that I'm working on my bike at the moment (well now I'm making dinner, but anyway)
Like this information a lot.
chaconne
Well-known member
Roberta,
Thanks for pointing this out. It seems that there really may be a proven advantage to the On-X. I will email my cardio about this. As pellicle stated, it makes me feel a little bit more comfortable being in the low range as well.
Thanks for pointing this out. It seems that there really may be a proven advantage to the On-X. I will email my cardio about this. As pellicle stated, it makes me feel a little bit more comfortable being in the low range as well.
chaconne
Well-known member
This abstract only mentions the Warfarin-Aspirin part of the study. Does anyone know what happened to the Plavix-Aspirin study?
Thanks for posting Roberta, since I just got my new on-x valve 9 days ago, I want to hear all I can about the current studies concerning it ant the future for no Coumadin. Again thanks. Kim
TheGymGuy
Well-known member
great study. thanks for sharing.
Kim: I don't know what ' it ant the future for no Coumadin' means. Obviously, there are some letters or words missing.
Personally, even with an On-X valve, I'd still probably feel safer taking a little warfarin until there are lots of studies that say that Aspirin is adequate to prevent clotting. To me, it's not worth the risk of having to put up with the very minor (usually) inconvenience of taking warfarin when compared to the potentially debilitating or fatal outcome from clotting on the valve.
Personally, even with an On-X valve, I'd still probably feel safer taking a little warfarin until there are lots of studies that say that Aspirin is adequate to prevent clotting. To me, it's not worth the risk of having to put up with the very minor (usually) inconvenience of taking warfarin when compared to the potentially debilitating or fatal outcome from clotting on the valve.
Lederman40
Member
My cardio has been following this closely, but I'm still of his school of thought. Bleeding is much easier to address than a stroke. Oversimplifying it I know, but the man has a point.
ElectLive
Well-known member
I put this in the related thread....just wanted to add more directly here: The Plavix/Asprin arm of PROACT finally completed enrollment about a month ago. While that's an important milestone, all is not quite what it seems, ON-X actually had to back their way into it:
The original enrollment targets for PROACT were 200 patients in each arm - so, in other words, there would be both 200 patients on Plavix/Aspirin and 200 matched up on standard Warfarin treatment (the control group). The follow-up was to be a minimum of 5 years, which would have been 1000 patients years, enough for FDA approval (800 minimum).
Well, in early 2011, they were only up to 40 patients of each, so enrollment going very very slow...not even 25% at the five year mark. At that point, the enrollment targets were changed to 150 patients followed for 6.7 years. The patient year math still worked the same, and I guess if the FDA was ok with this, it shouldn't be called "cheating", but I don't know... Because, guess what, it happened again. As of early 2013, enrollment was still only up to 90 patients each, so the targets were changed yet again, this time to 100 patients followed for 8 years. So, a few months later, they finally had the 20 additional patients needed to fill out the new trial target.
I guess it's pretty obvious why this needed to be done...the study had been going on since 2006, so patients already active in the trial were already completing their 5 year requirement, yet the trial itself had no foreseeable way to meet enrollment targets within even the next several years. So they just changed the targets... :rolleyes2:
Now, while I'm being slightly cynical here, more seriously, I do think this is kind of bad news for the future Plavix/Aspirin results. Yes, the FDA patient year requirement for heart valves is pretty well proven out, but when evaluating pretty low risk events that can often be more patient driven than valve/treatment driven, obviously the more patients in a study the better, and 100 patients just "feels" like a low number. It's very tough, though, with limited valve patients, and more importantly, limited numbers willing to risk potential stroke on an unproven regimen. It's just interesting to me how different the process is for FDA approved medicines for more common heart conditions: as a comparison, the trials for another method of replacing Warfarin (Pradaxa - Afib) involved 18,000 patients!
ElectLive
Well-known member
For those with interest in the details, full copy of the Interim Results (for Reduced Anticoagulation) as presented can be found here: http://webcast.aats.org/2013/files/Monday/20130506_auditorium_0745_07.45%20John%20D.%20Puskas.pdf. I posted a similar data package (earlier in the study - http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_425310.pdf) about a year ago that I wasn't sure was really meant for public disclosure, but no worries this time, On-X even has the video of this presentation on their Facebook page!
There is a lot to discuss, and I'm short on time, but a few quick comments:
1. The Low-Risk arm enrollment is included here also, as I'd mentioned in the previous post, but even more interesting is the # of patients classified as "Removed". Of 519 patients originally enrolled in Low Risk, 302 were removed. Lots of factors could lead to removal such as patient or doctor withdrawal, a complication event, etc but it would appear that the bulk of the removals in the Low Risk group are due to inadequate platelet response to Plavix and/or Aspirin 325. The Removal percentage is much much lower in the other arms, where all the other factors would be expected to be more or less the same.
2. The disparity in stroke events seems to be decreasing as time goes on. The initial data package showed a more pronounced effect of the reduced INR on stroke/TIA events than the most recent data. Some are equalizing while others are only slightly higher, and it appears are now close enough to not be "statistically significant" in the words of the medical community. Although I'm sure the few extra patients having events would consider them significant...
3. I wish the most recent data set was more complete. One of the best slides from the earlier data was the one that illustrated INR values at time of event (both bleeding and stroke). It very much seemed to show that the majority of events were actually happening outside the study ranges (both test and control)...
There is a lot to discuss, and I'm short on time, but a few quick comments:
1. The Low-Risk arm enrollment is included here also, as I'd mentioned in the previous post, but even more interesting is the # of patients classified as "Removed". Of 519 patients originally enrolled in Low Risk, 302 were removed. Lots of factors could lead to removal such as patient or doctor withdrawal, a complication event, etc but it would appear that the bulk of the removals in the Low Risk group are due to inadequate platelet response to Plavix and/or Aspirin 325. The Removal percentage is much much lower in the other arms, where all the other factors would be expected to be more or less the same.
2. The disparity in stroke events seems to be decreasing as time goes on. The initial data package showed a more pronounced effect of the reduced INR on stroke/TIA events than the most recent data. Some are equalizing while others are only slightly higher, and it appears are now close enough to not be "statistically significant" in the words of the medical community. Although I'm sure the few extra patients having events would consider them significant...
3. I wish the most recent data set was more complete. One of the best slides from the earlier data was the one that illustrated INR values at time of event (both bleeding and stroke). It very much seemed to show that the majority of events were actually happening outside the study ranges (both test and control)...
Is there any evidence of animal studies before this protocol went to humans?
ElectLive
Well-known member
Good question...you know On-X publishes generally everything they've ever done, but I've never seen that animal study of any PROACT protocol ever was undertaken directly by them. That doesn't mean it didn't of course! When the very small aspirin only study took place in Germany a decade or so ago (later halted), there was mention beforehand of testing in sheep, specifically designed to force thrombosis :mad2: , and the results were said to have been superior to the other mechanical valves with identical testing, but that was completely unrelated to protocol.
However, there was an independent study in Germany from roughly the same time period that documented a Plavix/Aspirin protocol in rabbits, so perhaps that may have been related, even though it was not specific to On-X (or Medical Carbon Research Institute as it was generally known at the time). Anyway, the official press release of PROACT only mentions approval based on "existing clinical data and the submitted protocol" so not really sure.
Back to your question, though, guess what the folks at St. Jude's have also been up to... In the last 5-10 years, there has been a study using pigs that tested a modified St. Jude valve with various models of an Aspirin/Plavix protocol, and also a pilot study with a very limited human group. I haven't come across any indications of any push for a full fledged trial, though...
ElectLive
Well-known member
Here's another article that covered some of the follow-up discussion to the presentation of the On-X Reduced Anticoagulation results: http://www.anticoagulationhub.com/topics/dvtpe/single-article/less-aggressive-anticoagulation-appears-safe-after-high-risk-aortic-valve-replacement/16276dc4b8395bf5bb5f5d33a38c8b15.html. A well known surgeon from The Netherlands, Pieter Kappetein, had been invited as a discussant, and for those that don't know, the Re-Align trial (also now halted) he was part of is the one where Pradaxa was being substituted for Warfarin in mechanical valve patients. Anyway, here's a portion of the full article linked above, some pretty interesting "off-record" discussion:
Invited discussant Dr. A. Pieter Kappetein, a member of the RE-ALIGN trial steering committee and professor of thoracic surgery at Erasmus Medical Center in Rotterdam, the Netherlands, said the number of patients in the analysis [PROACT] was extremely low and questioned the validity of combining bleeding and thromboembolic events in the primary endpoint.
"In this study, you mix the efficacy endpoint with the safety endpoints," he said, observing that they move in opposite directions. In light of such large-scale trials as ARISTOTLE and RELY, he asked whether PROACT should be considered a pilot trial and whether a new trial, designed with roughly 8,000 patients, should be performed that would also include newer anticoagulation agents to adequately evaluate reduced anticoagulation in mechanical valves." Is it not potentially dangerous if we do not know what the increase is for thrombosis and follow your conclusions?" he added.
Dr. Puskas said he shared Dr. Kappetein’s concern about the noninferiority design of the trial and that it was a topic of great discussion with the Food and Drug Administration (FDA). He also agreed that thrombotic events and bleeding events move in the opposite direction. "What we are really looking for is to determine the sweet spot where those two curves intersect," he said. "While it is theoretically and intellectually correct to say that thrombosis is the efficacy issue and hemorrhage is the safety issue, we are obliged to combine those for two reasons. "The first is practical; no company will sponsor an 8,000-patient trial, and second, this is, in fact, a trade-off in the minds of patients and clinicians. So, it is a relevant clinical endpoint – the unholy composite, if you will – of thrombosis and hemorrhage."
Finally, a member of the audience asked whether the results would hold up with standard management because universal point-of-care home testing is not the "real world" in the United States. Dr. Puskas replied that it is in Scandinavia and other parts of the world, and admonished American clinicians, including himself, "to catch up to what should be standard of care." He noted that, based on the roughly 53,000 INR readings in PROACT, controlling INR within your range was more important in terms of adverse events, particularly hemorrhagic events, than what arm patients were assigned to.
"Home monitoring is available, it’s not high tech and it’s much easier for patients," he said. "To be perfectly blunt, there’s really no excuse for us not using it uniformly in America. Quite frankly, it is a conflict of interest between local caregivers and their patients’ well-being. There is a small revenue stream to cardiology offices and primary care doctors running Coumadin clinics, and that is keeping us in the system that we have now rather than home monitoring through bigger, centralized Coumadin clinics."
"In this study, you mix the efficacy endpoint with the safety endpoints," he said, observing that they move in opposite directions. In light of such large-scale trials as ARISTOTLE and RELY, he asked whether PROACT should be considered a pilot trial and whether a new trial, designed with roughly 8,000 patients, should be performed that would also include newer anticoagulation agents to adequately evaluate reduced anticoagulation in mechanical valves." Is it not potentially dangerous if we do not know what the increase is for thrombosis and follow your conclusions?" he added.
Dr. Puskas said he shared Dr. Kappetein’s concern about the noninferiority design of the trial and that it was a topic of great discussion with the Food and Drug Administration (FDA). He also agreed that thrombotic events and bleeding events move in the opposite direction. "What we are really looking for is to determine the sweet spot where those two curves intersect," he said. "While it is theoretically and intellectually correct to say that thrombosis is the efficacy issue and hemorrhage is the safety issue, we are obliged to combine those for two reasons. "The first is practical; no company will sponsor an 8,000-patient trial, and second, this is, in fact, a trade-off in the minds of patients and clinicians. So, it is a relevant clinical endpoint – the unholy composite, if you will – of thrombosis and hemorrhage."
Finally, a member of the audience asked whether the results would hold up with standard management because universal point-of-care home testing is not the "real world" in the United States. Dr. Puskas replied that it is in Scandinavia and other parts of the world, and admonished American clinicians, including himself, "to catch up to what should be standard of care." He noted that, based on the roughly 53,000 INR readings in PROACT, controlling INR within your range was more important in terms of adverse events, particularly hemorrhagic events, than what arm patients were assigned to.
"Home monitoring is available, it’s not high tech and it’s much easier for patients," he said. "To be perfectly blunt, there’s really no excuse for us not using it uniformly in America. Quite frankly, it is a conflict of interest between local caregivers and their patients’ well-being. There is a small revenue stream to cardiology offices and primary care doctors running Coumadin clinics, and that is keeping us in the system that we have now rather than home monitoring through bigger, centralized Coumadin clinics."
This is very useful information, and I appreciate the quotes that you pulled from the article. What primarily concerns me is talk about a 'sweet spot' between thrombotic events and hemorrhagic events. This 'sweet spot' implies that there is some acceptable amount of both. As someone who had a thrombotic event, I don't think that there's a sweet spot for that -- other than entire avoidance of that risk.
There is a pretty well established sweet spot using warfarin -- it substantially reduces the risk of thrombotic events (if your meter and strips are accurate), and also avoids the risk of major hemorrhagic events. For many of us, that range is 2.5-3.5. I still have a question about whether having a valve - even one that presents absolutely 0 thrombotic risk (and no such valve exists) - would be adequate reason to reduce or eliminate an anticoagulant. IF such a valve is developed, I still wouldn't want to be one of the 8000 in a test group who is running a possible risk of TIA or Stroke. I'm not normally conservative, but when my life is on the line, and the possibility of a stroke or death significantly outweighs the minimal issues related to taking warfarin, I'd rather take the warfarin - even if it may not be necessary.
There is a pretty well established sweet spot using warfarin -- it substantially reduces the risk of thrombotic events (if your meter and strips are accurate), and also avoids the risk of major hemorrhagic events. For many of us, that range is 2.5-3.5. I still have a question about whether having a valve - even one that presents absolutely 0 thrombotic risk (and no such valve exists) - would be adequate reason to reduce or eliminate an anticoagulant. IF such a valve is developed, I still wouldn't want to be one of the 8000 in a test group who is running a possible risk of TIA or Stroke. I'm not normally conservative, but when my life is on the line, and the possibility of a stroke or death significantly outweighs the minimal issues related to taking warfarin, I'd rather take the warfarin - even if it may not be necessary.
